Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment

Abstract

Fatty Acid Desaturase-1 (FADS1) or delta 5 desaturase (D5D) is a rate-limiting enzyme involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), i.e., arachidonic acid (ARA) and eicosapentaenoic (EPA). These LC-PUFAs and their metabolites play essential and broad roles in cancer cell proliferation, metastasis, and tumor microenvironment. However, the role of FADS1 in cancers remains incompletely understood. Utilizing The Cancer Genome Atlas (TCGA) database, we explored the role of FADS1 across different cancer types using multiple bioinformatics and statistical tools. Moreover, we studied the impact of a FADS1 inhibitor (D5D-IN-326) on proliferation of multiple cancer cell lines. We identified that FADS1 gene is a predictor for cancer survival in multiple cancer types. Compared to normal tissue, the mRNA expression of FADS1 is significantly increased in primary tumors while even higher in metastatic and recurrent tumors. Mechanistically, pathway analysis demonstrated that FADS1 is associated with cholesterol biosynthesis and cell cycle control genes. Interestingly, FADS1 expression is higher when TP53 is mutated. Tumors with increased FADS1 expression also demonstrated an increased signatures of fibroblasts and macrophages infiltration among most cancer types. Our in vitro assays showed that D5D-IN-326 significantly inhibited cell proliferation of kidney, colon, breast, and lung cancer cell lines in a dose-dependent manner. Lastly, single nucleotide polymorphisms (SNPs) which are well-established expression quantitative trait loci (eQTLs) for FADS1 in normal human tissues are also significantly correlated with FADS1 expression in tumors of multiple tissue types, potentially serving as a marker to stratify cancer patients with high/low FADS1 expression in their tumor tissue. Our study suggests that FADS1 plays multiple roles in cancer biology and is potentially a novel target for precision cancer treatment.

Postoperative Metabolic Phenoreversion in Clear Cell Renal Cell Carcinoma

“…Other authors showed that ccRCC tissue samples exhibited higher levels of linoleic acid compared to normal renal tissue. , Taking into account the role of this essential fatty acid as a precursor of several long-chain polyunsaturated fatty acids (LC-PUFAs) involved in immunity regulation and inflammatory response, its downregulation after surgery in ccRCC patients with good prognosis may be related to an improved outcome. Moreover, high mRNA expression of fatty acid desaturase-1 (FADS1, a key enzyme involved in the biosynthesis of LC-PUFAs) in tumors, was associated with worse overall survival and disease-free survival, in particular for ccRCC, papRCC, and chRCC patients . Although more studies are needed to unravel the dietary lipid influence in ccRCC, , our results highlight linoleic acid and its metabolism as interesting targets to be monitored during patient follow-up.…”

“…Moreover, high mRNA expression of fatty acid desaturase-1 (FADS1, a key enzyme involved in the biosynthesis of LC-PUFAs) in tumors, was associated with worse overall survival and disease-free survival, in particular for ccRCC, papRCC, and chRCC patients. 61 Although more studies are needed to unravel the dietary lipid influence in ccRCC, 62,63 our results highlight linoleic acid and its metabolism as interesting targets to be monitored during patient follow-up.…”

A Robust Ferroptosis-Related Prognostic Model Associated With Immune Infiltration, Tumor Mutation Burden in Bladder Cancer

“…3A). Fatty Acid Desaturase 1(FADS1) plays a regulatory role in the anabolism of long-chain polyunsaturated fatty acids (44), which was rst cloned in 1999 and was found on the human genome chromosome 11q12-11q13.1. ( 45).…”

Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response

“…PUFAs and their derivatives have been implicated to play broad functions in cancer impacting various stages from tumorigenesis to progression and metastasis (24)(25)(26)(27)(28). Previous research has shown that Fatty Acid Desaturase 1 (FADS1), a rate-limiting enzyme in LC-PUFA bioproduction, plays a significant role in the growth of various cancer cells (13) and is overexpressed in colon, pancreas, breast, and laryngeal cancers (29). However, whether the LC-PUFA production, controlled by FADS1, plays a similar role as MUFAs remains to be explored.…”